4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N-β-diphenylbenzenebutanamide of formula I hereinafter referred to as DKT III, is a key intermediate for the synthesis of Atorvastatin

U.S. Pat. No. 4,681,893, U.S. Pat. No. 5,124,482, U.S. Pat. No. 5,216,174, U.S. Pat. No. 5,097,045 disclose the process for the preparation of Atorvastatin including the process for the preparation of compound of formula I by reacting 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentamide with 4-fluorobenzaldehyde in the presence of a catalyst such as 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride, 3,4-dimethyl-5-(2-hydroxy-ethyl)-thiazolium iodide, 3-ethyl-4-(2-hydroxyethyl)-4-methylthiazolium bromide, thiamine hydrochloride and the base selected from N,N-diisopropylethylamine, pyridine, N,N-dimethylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, N,N,N′,N′-tetramethylethylenedimine.
WO03/004457 discloses the process for making 4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N-β-diphenylbenzenebutanamide by reacting 2-bromo-1-(4-fluorophenyl)-2-phenone (a compound of formula II) with 4-methyl-3-oxo-N-phenylpentamide (a compound of formula III) by using a highly polar solvent system comprising DMF, ethanol and methanol. Product is isolated by precipitation with solvent like n-hexane. The remaining soluble material is recovered by chromatographic separation. The compound is obtained as diastereoisomeric mixture in a ratio of about 3:1 to 4:1 including unknown impurities. In case of mixture of ratio 3:1 and 4:1 the yield of DKT III is 75% and 80% respectively and the other impurity constituents of the remaining 20-25% mixture have neither been isolated nor characterized.

Following schematic representation depicts different synthetic schemes for the preparation of compound of the formula I according to the references cited hereinbefore or after.

The compound of formula III was described in JOC, 1978, 43, 2087-2088, Synthesis 1992, 1213-1214, Chem. Pharm. Bull. 1987, 35, 1860-1870
WO2006/021968, discloses a process for DKT III comprising a reaction between bromo-4-methyl-3-oxo pentanoic acid phenylamide and 1-(4-fluoro phenyl)-2-phenyl ethanone. It discloses α-[2-methyl-1-oxopropyl]-γ-oxo-N-β-diphenylbenzene butanamide of formula IV hereinbefore and hereinafter referred as desfluoro and difluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N-β-diphenylbenzene butanamide of formula V hereinbefore and hereinafter referred as difluoro as impurities. It neither isolates nor characterizes any other impurity.
Other relevant references may include: KR 10-2004-0001435, J. Labelled Cpd. Radiopharm. 42, 121-127, 1999, and KR 20050124322.
U.S. Pat. No. 5,216,174 discloses the preparation of 4-Methyl-3-oxo-N-phenylpentamide of formula III by reacting Methyl 4-methyl-3-oxopentaonate with aniline in toluene as a solvent in the presence of ethylene diamine as a base. The product is isolated after 10 days in 69% yield. WO200304457 also prepares a compound of formula III in accordance with the process of U.S. Pat. No. 5,216,174.
Purity of Atorvastatin is dependent on the purity of DKT III, it is, therefore, important to control impurities at this stage. Prior art reports desfluoro and difluoro as impurities that affect the purity of Atorvastatin, J. Labelled Cpd. Radiopharm. 42,121-127, 1999 discloses that the presence of trace amounts of water during the synthesis of DKT III results in the formation of α-[2-methyl-1-oxopropyl]-γ-oxo-N-β-diphenylbenzene butanamide hereinbefore and hereinafter referred as desfluoro of formula IV as a major impurity; prior art also discloses the formation of difluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N-β-diphenylbenzene butanamide hereinbefore and hereinafter referred as difluoro of formula V as an impurity during the formation of DKT III.

The present invention discloses a process for preparing DKT III in 99:1 diastereoisomeric mixture comprising up to 1% total impurities with the desfluoro impurity of about 0.1% and the difluoro impurity about 0.05%. The invention also provides a process for the isolation and characterization of unknown impurity formed during the formation of DKT III. The newly characterized impurity is of formula VI and is up to 0.1%.
Prior art also discloses a process for making 4-Methyl-3-oxo-N-phenylpentamide of formula III that requires 10 days for the isolation of the product and is carried out in a solvent. The present invention discloses a process for making 4-Methyl-3-oxo-N-phenylpentamide of formula III which does not require any solvent and product is isolated in a single day reducing the reaction time 10 folds thus making it more efficient and economical.
During the preparation of DKT III comprising reaction between compounds of formula II & III, there exists a possibility of formation of compounds of formulae VI, VII. This could be based on the fact that compound of formula III possesses tautomerism and also exists as enol form as shown below.

However compound of the formula VII as depicted below is enol form of DKT III. Keto enol forms always exist as equilibrium mixtures and it is impossible to isolate either of them in pure form. Therefore formation of VII as an impurity during the preparation of DKT III is forbidden. The existence of keto and enol form can be observed only by the spectroscopic techniques such as NMR.

Therefore probable impurity in DKT III due to the existence of enol form is 3-[2-(4-Fluorophenyl)-2-oxo-1-phenyl-ethoxy]-4-methyl-pent-2-enoic acid phenylamide hereinabove and hereinbelow referred to as O-alkylated impurity, of formula VI

Though O-alkylated is not listed in the prior art of DKT III and Atorvastatin, it is nevertheless important to minimize it in DKT III in the interest of higher purity and good yield of Atorvastatin.
In the present invention, inventors have studied and revealed that O-alkylation of enol tautomer to form O-alkylated impurity of formula VI affect the purity and yield of DKT III considerably.